Various publications, including patents, published applications, technical articles and scholarly articles are cited throughout the specification. Each of these cited publications is incorporated by reference herein, in its entirety. Any publication referred to by number in the specification is fully cited at the end of the specification.
Inappropriate or excessive activation of the human complement system is implicated in many clinical disorders.[1] Compstatin, a 13-residue cyclic peptide originally discovered via phage-display library screening (Ile-[Cys-Val-Val-Gln-Asp-Trp-Gly-Ala-His-Arg-Cys]-Thr; cyclic C2-C12; SEQ ID NO:1), interacts with the complement component C3 and its activation fragment C3b, and broadly inhibits complement activation.[2,3] The central role of C3 in complement initiation and amplification pathways renders C3 inhibitors an attractive option for the treatment of a wide range of complement-related conditions, and compstatin analogs have shown promise in disorders ranging from sepsis and biomaterial-induced thromboinflammation to transplantation.[3-6] Whereas an early analog of compstatin (POT-4, Potentia Pharmaceuticals) is in clinical development for the local treatment of age-related macular degeneration, the pharmacokinetic profile of this analog may limit systemic applications. New generations of compstatin derivatives with enhanced inhibitory activity and plasma residence have therefore been developed.[7,8] Backbone N-methylation resulted in analog Cp20 (Ac-Ile-[Cys-Val-Trp(Me)-Gln-Asp-Trp-Sar-Ala-His-Arg-Cys]-mIle-NH2; SEQ ID NO:2) that showed 10-fold improved affinity.[8] Introducing an additional amino acid at the N-terminus of Cp20, thereby extending the target binding site, produced the analog Cp40 ((D)Tyr-Ile-[Cys-Val-Trp(Me)-Gln-Asp-Trp-Sar-Ala-His-Arg-Cys]-mIle-NH2; SEQ ID NO:3) with subnanomolar binding affinity for C3 (KD=0.5 nM). Importantly, pharmacokinetic evaluation in non-human primates (NHP) revealed that these next-generation compstatin analogs follow target-driven elimination kinetics and feature half-life values of up to 12 h, thereby exceeding those typically reported for peptide drugs.[7] Cp40 has shown promise in preclinical models of paroxysmal nocturnal hemoglobinuria and periodontal disease,[9,10] and is currently developed for a variety of systemic disorders.[11] Whereas suitable inhibitor levels for chronic treatment could be achieved via subcutaneous application of Cp40,[9] further extension of its plasma residence is considered beneficial through a decrease in dose intervals.
Among the various strategies to improve the half-life of peptidic drugs, the coupling to albumin-binding tags appears particularly promising.[12] Albumin constitutes ˜60% of the total plasma protein pool and has a long circulation residence (t½˜20 d); binding to serum albumin has therefore been recognized as an attractive route to extend the plasma residence of biopharmaceuticals.[12,13] Alongside direct coupling approaches,[13,14] several affinity tags based on albumin-binding peptides or molecules (ABP and ABM, respectively) have been developed that allow non-covalent interaction with circulating albumin.[15-19] Chimeras of a compstatin derivative with an ABP have been successfully constructed,[20] yet their synthesis is demanding, given the involvement of two cyclic peptides. Low molecular weight molecules are available. For instance two previously described naphthalene acylsulfonamide[17] and diphenyl-cyclohexanol phosphate ester[18,21] tags have been shown to improve the plasma half-life of therapeutic peptides.[18] One of these tags is being used clinically in the case of MS-325 (gadofosveset trisodium; Ablavar®, Lanteus Medical Imaging), a rationally designed magnetic resonance imaging (MRI) contrast agent with prolonged intravascular half-life (18.5±3 h in human).[21]
In view of the information above, it is clear that a need exists for additional, preferably cost-effective, ways of improving the plasma residence of compstatin and extending its use in systemic indications.